Cytokines and immune cells mediate specific physiological mechanisms or pathways, e.g., pathways leading to the various inflammatory disorders. Human thymic stromal lymphopoietin (TSLP) is an IL-7-like cytokine that is produced from human epithelial cells. It promotes B-cell differentiation and also can co-stimulate both thymocytes and mature T-cells. TSLP binds to a specific heterodimeric receptor on human CD11c+ dendritic cells (DC's). The receptor heterodimer consists of a common gamma-like receptor chain (TSLP receptor; TSLPR) and the IL-7R-α chain. See, e.g., Tonozuka et al., Cytogenet. Cell Genet. 93:23-25, 2001; Pandey et al., Nat. Immunol. 1:59-64, 2000; L. S. Park et al., J. Exp. Med. 192:659-670, 2000; and Reche et al., J. Immunol. 167:336-343, 2001. Ligand binding to the receptor induces DC's to secrete TH2-attracting chemokines, TARC (thymus and activation-regulated chemokine) and MDC (macrophage derived chemokine). In addition, TSLP also induces potent DC activation, naïve CD4+ T cell expansion, and subsequent polarization to a TH2 phenotype, producing pro-allergic cytokines interleukin 4 (IL-4), IL-5, IL-13 and tumor necrosis factor-α.
It was also found that TSLP signaling results in activation of the Stat5 transcription factor. Furthermore, both acute and chronic atopic dermatitis patients have been reported to over-express TSLP in skin lesions, suggesting that TSLP expression is associated with allergic inflammation in vivo. Aside from skin keratinocytes, high level of TSLP expression have also been found in bronchial epithelial cells, smooth muscles and lung fibroblasts, supporting a potential role for TSLP in respiratory allergic indications as well. Moreover, IgE activated mast cells express very high level of TSLP, a mechanism which could participate in the maintenance of the TH2 phenotype.
About 20% of the population in the Western countries suffers from inflammatory disorders, e.g., the allergic diseases, which include asthma, rhinitis, atopic dermatitis, and food allergy. From 50% to 80% of the patients with atopic dermatitis have or develop asthma or allergic rhinitis. To date, there is no cure for allergy induced asthma, atopic dermatitis, and allergic rhinitis. Current treatments, such as beta-2 adrenoceptor antagonists for asthma, Elidel for atopic dermatitis, and H1-antihistamine for allergic rhinitis, are used to target the symptoms. Thus, there is an increased need in the art for better therapies to treat these inflammatory disorders, in particular, allergic inflammation. The present invention addresses this and other problems.